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Neurophysiology of Orofacial Pain Koichi Iwata, Mamoru Takeda, Seog Bae Oh, and Masamichi Shinoda Abstract It is well known that unmyelinated C-bers and small-diameter Aδ-bers innervate the orofacial skin, mucous membrane, orofacial muscles, teeth, tongue, and temporomandibu- lar joint. Peripheral terminals consist of free nerve endings, and thermal and mechanical receptors such as transient receptor potential (TRP) channels and purinergic receptors exist in nerve endings. Ligands for each receptor are released from peripheral tissues following a variety of noxious stimuli applied to the orofacial region and bind to these receptors, following which action potentials are gener- ated in these bers and conveyed mainly to the trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). Neurons receiving noxious inputs from the orofacial regions are somatotopically orga- nized in the Vc and C1-C2. The third branch (mandibular nerve) of the trigeminal nerve innervates the dorsal portion of the Vc, and the rst branch (ophthalmic nerve) of the tri- geminal nerve innervates the ventral part of the Vc; the middle portion of them receives the second branch (maxillary nerve) of the trigem- inal nerve. Various neurotransmitters such as glutamate and substance P (SP) are released from primary afferent terminals and bind to receptors such as AMPA and NMDA gluta- mate receptors and neurokinin 1 receptors in Vc and C1-C2 nociceptive neurons. Further, noxious information from the orofacial region reaching Vc and C1-C2 is sent to the somato- sensory and limbic cortices via the ventral pos- terior medial thalamic nucleus (VPM) and medial thalamic nuclei (parafascicular nucleus, centromedial nucleus, and medial dorsal nucleus), respectively, and nally, orofacial pain sensation is perceived. It is also known that descending pathways in the brain act on Vc and C1-C2 nociceptive neurons to modu- late pain signals. Under pathological condi- tions such as trigeminal nerve injury or orofacial inammation, trigeminal ganglion (TG) neurons become hyperactive, and a bar- rage of action potentials is generated in TG neurons, and these are sensitized a long time K. Iwata (*) M. Shinoda Department of Physiology, School of Dentistry, Nihon University, Tokyo, Japan e-mail: [email protected]; [email protected] M. Takeda Laboratory of Food and Physiological Sciences, Department of Food and Life Sciences, School of Life and Environmental Sciences, Azabu University, Sagamihara, Kanagawa, Japan e-mail: [email protected] S.B. Oh Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, Republic of Korea e-mail: [email protected] # Springer International Publishing AG 2017 C.S. Farah et al. (eds.), Contemporary Oral Medicine, DOI 10.1007/978-3-319-28100-1_8-3 1

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Page 1: Neurophysiology of Orofacial Pain - Berandafkg.usu.ac.id/images/Bahan_Kuliah/Buku_McCullough/... · Neurophysiology of Orofacial Pain Koichi Iwata, Mamoru Takeda, Seog Bae Oh, and

Neurophysiology of Orofacial Pain

Koichi Iwata, Mamoru Takeda, Seog Bae Oh, andMasamichi Shinoda

AbstractIt is well known that unmyelinated C-fibersand small-diameter Aδ-fibers innervate theorofacial skin, mucous membrane, orofacialmuscles, teeth, tongue, and temporomandibu-lar joint. Peripheral terminals consist of freenerve endings, and thermal and mechanicalreceptors such as transient receptor potential(TRP) channels and purinergic receptors existin nerve endings. Ligands for each receptor arereleased from peripheral tissues following avariety of noxious stimuli applied to theorofacial region and bind to these receptors,following which action potentials are gener-ated in these fibers and conveyed mainly tothe trigeminal spinal subnucleus caudalis(Vc) and upper cervical spinal cord (C1-C2).

Neurons receiving noxious inputs from theorofacial regions are somatotopically orga-nized in the Vc and C1-C2. The third branch(mandibular nerve) of the trigeminal nerveinnervates the dorsal portion of the Vc, andthe first branch (ophthalmic nerve) of the tri-geminal nerve innervates the ventral part of theVc; the middle portion of them receives thesecond branch (maxillary nerve) of the trigem-inal nerve. Various neurotransmitters such asglutamate and substance P (SP) are releasedfrom primary afferent terminals and bind toreceptors such as AMPA and NMDA gluta-mate receptors and neurokinin 1 receptors inVc and C1-C2 nociceptive neurons. Further,noxious information from the orofacial regionreaching Vc and C1-C2 is sent to the somato-sensory and limbic cortices via the ventral pos-terior medial thalamic nucleus (VPM) andmedial thalamic nuclei (parafascicular nucleus,centromedial nucleus, and medial dorsalnucleus), respectively, and finally, orofacialpain sensation is perceived. It is also knownthat descending pathways in the brain act onVc and C1-C2 nociceptive neurons to modu-late pain signals. Under pathological condi-tions such as trigeminal nerve injury ororofacial inflammation, trigeminal ganglion(TG) neurons become hyperactive, and a bar-rage of action potentials is generated in TGneurons, and these are sensitized a long time

K. Iwata (*) • M. ShinodaDepartment of Physiology, School of Dentistry, NihonUniversity, Tokyo, Japane-mail: [email protected];[email protected]

M. TakedaLaboratory of Food and Physiological Sciences,Department of Food and Life Sciences, School of Life andEnvironmental Sciences, Azabu University, Sagamihara,Kanagawa, Japane-mail: [email protected]

S.B. OhDepartment of Neurobiology and Physiology, School ofDentistry, Seoul National University, Seoul, Republic ofKoreae-mail: [email protected]

# Springer International Publishing AG 2017C.S. Farah et al. (eds.), Contemporary Oral Medicine,DOI 10.1007/978-3-319-28100-1_8-3

1

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after the hyperactivation of TG neurons. Fur-thermore, there is an increase in Vc and C1-C2neuronal activities, and these neurons can besensitized in association with TG-neuron sen-sitization, and then orofacial pain hypersensi-tivity can occur. Recent studies have alsoreported that glial cells are involved in patho-logical orofacial pain states related to trigemi-nal nerve injury and orofacial inflammation.Peripheral and central mechanisms of orofacialpain under physiologic and pathologic condi-tions are overviewed in this chapter, and futureinsights regarding the pathogenesis of persis-tent orofacial pain are discussed.

KeywordsTrigeminal nerve •Orofacial pain •Brainstem •Medial system • Lateral system • Descendingmodulation • Persistent pain

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Primary Afferent Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . 3Physiology of Orofacial Nociceptors . . . . . . . . . . . . . . . . . 3Receptor Mechanisms of Trigeminal Primary

Afferent Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Trigeminal Ganglion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Pathological Changes in Trigeminal Ganglion . . . . . . . 6

Brainstem Nociceptive Neurons . . . . . . . . . . . . . . . . . . . . 7Trigeminal Spinal Nucleus and Upper Cervical

Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Physiology of Trigeminal Nociceptive Neurons . . . . . 10Neurotransmitters in Brainstem Nociceptive

Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Pathological Changes in Brainstem Nociceptive

Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Higher Brain Function Regulating OrofacialNociception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Ascending Orofacial Pain Pathways . . . . . . . . . . . . . . . . . . 14Sensory-Discriminative and Motivational and

Affective Aspects of Pain . . . . . . . . . . . . . . . . . . . . . . . . . 14Human Brain Function for Orofacial Pain

Sensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Descending Modulation of Orofacial Pain . . . . . . . . . 16Descending Pathways Influencing Orofacial Pain . . . . 16Modulation of Trigeminal Nociceptive Neurons . . . . . 17Pathological Changes in the Descending System . . . . 17

Conclusion and Future Directions . . . . . . . . . . . . . . . . . . 18

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Introduction

The trigeminal nervous system is known to haveunique structures and functions for processingorofacial nociception as well as non-noxious sen-sations in comparison to the spinal nervous sys-tem. Oral mucous membrane, tongue, tooth pulp,gingiva, and temporomandibular joints are inner-vated by small-diameter Aδ-fibers and unmyelin-ated C-fibers that process orofacial nociception.Peripheral terminals of these fibers are composedof free nerve endings, and various receptors areexpressed on the membrane surface of nerve end-ings, and these receptors act as sensors respondingto various noxious stimuli such as heat, cold, orchemical stimulus (Iwata et al. 2011a). For exam-ple, it has been well documented in recent decadesthat transient receptor potential vanilloid1 (TRPV1) channel is cloned, and functions ofthis channel have been evaluated (Mickle et al.2015). TRPV1 and TRPV2 channels are known tobe involved in heat sensation and TRPV3 andTRPV4 in a warm sensation, whereas transientreceptor potential ankyrin 1 (TRPA1) and M8are known to participate in cool and cold sensa-tions (Tominaga 2007). ATP and glutamate recep-tors have also been reported to be expressed infree nerve endings of C-fibers and are known tocontribute to orofacial nociception (Sessle 2011).Though piezo receptors have been reported to takepart in mechanical sensations, detailed mecha-nisms for mechanical sensation are still unknown(Woo et al. 2014).

Neuronal activity is conveyed along the affer-ents to the trigeminal spinal subnucleus caudalis(Vc) and upper cervical spinal cord (C1-C2), andnociceptive neurons in these areas are activatedfollowing various noxious stimuli applied to theorofacial regions (Sessle 2000). Vc and C1-C2nociceptive neurons are classified as widedynamic range (WDR) and nociceptive-specific(NS) neurons according to their response proper-ties to mechanical stimulation of the receptivefields (Iwata et al. 1999, 2001). The nociceptiveinformation is then conveyed to the somatosen-sory and limbic cortices via the ventral post-eromedial thalamic nucleus (VPM) and medial

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thalamic nuclei, respectively. The VPM-somato-sensory pathway is known to be involved in thesensory-discriminative aspect of pain, whereasmedial thalamic nuclei-limbic cortices pathwaysare involved in the motivational and affectiveaspect of pain, and some noxious information isalso conveyed to the limbic cortices via the para-brachial nucleus (Treede et al. 1999; Benarroch2001). At each level of ascending pathways, var-ious excitatory and inhibitory neurotransmittersare involved in synaptic transmission and modu-latory processes of orofacial nociceptive informa-tion. Projection neurons are known to expressexcitatory transmitters, whereas most of thelocal circuit neurons are inhibitory interneuronsexpressing inhibitory transmitters. Both excit-atory and inhibitory neurons are involved in themodulation of the neuronal excitability regardingorofacial nociception in higher central nervoussystem (CNS) regions. It is also well known thatthe descending system acts on nociceptive neu-rons at each level of the ascending pain pathways,and neuronal activity is modulated (Mason 2012).These ascending and descending pathways arethought to play a pivotal role involved in orofacialnociception.

Under pathological conditions, functional andmorphological changes are known to occur inthe peripheral and central nervous system. Notice-able shifts in the peripheral nervous system are theenhancement of neuronal activity and up- ordownregulation of various molecules within thetrigeminal ganglion (TG) associated with trigem-inal nerve injury or orofacial inflammation. It iswell known that neuropeptides and potassiumchannels are downregulated in TG neurons fol-lowing nerve transection, whereas sodium chan-nels are upregulated and accumulated at thestump end of the nerve resection (Mulder et al.1997; Pollema-Mays et al. 2013). High-frequencyaction potentials are generated in primary afferentneurons innervating orofacial territories aftertrigeminal nerve injury or orofacial inflammation.For a considerable time after trigeminal nervedamage or inflammation, TG neurons becomehyperactive and sensitized. Furthermore, satellitecells are activated within the TG in association

with hyperactivation of TG neurons (Tsuboi et al.2004; Nakagawa et al. 2010). Activated satelliteglial cells release various molecules, and TG neu-ronal activity can be further enhanced.

High-frequency action potentials are generatedin TG neurons and conveyed to the Vc and C1-C2neurons following trigeminal nerve injury ororofacial inflammation (Iwata et al. 1999, 2001).Microglial and astroglial cells in Vc and C1-C2are also activated in association with the hyper-activation of nociceptive neurons in these areas(Okada-Ogawa et al. 2009; Shibuta et al. 2012;Kiyomoto et al. 2013).

Within the TG, the functional interactionbetween neurons and glial cells is also thought tobe a key mechanism in the enhancement of neu-ronal activity under pathological conditions(Katagiri et al. 2012; Kaji et al. 2016). Theenhanced nociceptive information within the TGis sent to the higher CNS regions via the trigem-inal brain stem nuclei, resulting in severe pain inthe orofacial region. It is crucial to know thedetailed mechanisms underlying the pathogenesisof orofacial pain associated with trigeminal nerveinjury or orofacial inflammation to formulateappropriate diagnosis and treatment of persistentorofacial pain states.

In this chapter, peripheral mechanisms and theascending and descending pain pathways regard-ing orofacial pain are overviewed, and newknowledge on persistent orofacial pain mecha-nisms under pathological conditions is consid-ered, and the possible clinical relevance isdiscussed.

Primary Afferent Neurons

Physiology of Orofacial Nociceptors

The orofacial area is mainly innervated by threemain branches of the trigeminal nerve: ophthal-mic, maxillary, and mandibular (Fig. 1a). Themajority of trigeminal afferents are pseudo-unipolar with cell bodies lying in the TG, exceptproprioceptive afferents whose cell bodies lie inthe mesencephalic trigeminal nucleus (Davies

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Ophthalmicnerve

Ethmoidal nerve

Ciliary nerve

Lingual nerve

Inferior alveolar nerve

a

b c

Trigeminalganglion

Maxillarynerve

Mandibularnerve

Fig. 1 Trigeminal nerve and tooth pulp afferents.(a) Area innervated by trigeminal nerves (ophthalmic,maxillary, and mandibular nerves) (Revised in Purveset al., Neuroscience, 2004). (b) Molecular mechanisms ofneural theory. Thermo-TRP channels are functionallyexpressed by dental primary afferents. Action potentialsevoked by the influx of cations such as Ca2+ and Na+

through TRP channels transmit pain signals to the central

nervous system. (c) Molecular mechanisms of hydrody-namic theory. The fluid movement initiated by diverseexternal stimuli eventually activates mechanoreceptors indental primary afferents. Candidates of mechanosensitivemolecules are listed. Little is known about how the activa-tion of the low-threshold mechanoreceptor is eventuallyperceived as pain in the central nervous system(Reproduced and modified from Chung et al. (2013))

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et al. 2010). Free nerve endings that detect nox-ious stimuli are dispersed over the orofacial area,innervating the oral mucous membrane, tongue,tooth pulp, gingiva, masticatory muscle, or tem-poromandibular joint in the trigeminal system(Sessle 2000).

Nociceptors are specialized peripheral nerveterminals in a subset of sensory neurons anddetect noxious stimuli that have potential tocause tissue damage, which is then transducedinto electrical activity in nociceptors (Juliusand Basbaum 2001). Nociceptors are associa-ted with primary afferent axons with eitherlight myelination (Aδ-fibers) or unmyelination(C-fibers) that have a relatively slow conductionvelocity (3~30 m/s and <2 m/s, respectively),compared to Aβ-fibers (33~75 m/s) responsiblefor the conduction of activity evoked by innocu-ous mechanical stimuli such as proprioceptive andlight touch (see Table 1).

It is generally assumed that Aδ-fibers andunmyelinated C-fibers mediate first and secondpain evoked by noxious stimuli due to the tempo-ral difference in their respective conduction veloc-ity: the rapid, acute, sharp pain and the delayed,more diffuse, dull pain. Nociceptors, mostlyC-fibers, often respond to multiple kinds of stim-uli including intense heat, intense mechanicalstimuli, and various chemicals and are known as“polymodal nociceptors.”Nociceptors are usuallydivided into two groups: non-peptidergic neuronsthat bind with isolectin B (or IB4-positivenociceptors) and peptidergic neurons whichexpress substance P (SP) and calcitonin gene-related peptide (or IB4-negative nociceptors)(Basbaum et al. 2009).

It is important to note that the nociceptivefibers do not exclusively conduct nociceptiveinformation; some are also associated with the

transmission of itch sensation. Cheek model ofitch in the mouse provides a behavioral differen-tiation of chemicals that evoke predominantly itchin humans that elicit nociceptive sensations(Shimada and LaMotte 2008). The molecularmechanisms by which nociceptive fibers relayitch sensation to the CNS are now under extensiveinvestigation.

Receptor Mechanisms of TrigeminalPrimary Afferent Neurons

Nociceptors are unique in which they have theability to detect multiple types of noxious stimuli,including those of a physical or chemical nature.Therefore, nociceptors are equipped with diverserepertoires of transduction molecules that giverise to painful sensations by thermal, mechanical,or chemical stimuli, although with differentextents of sensitivity (Julius and Basbaum 2001).

TRPV1, the first pain receptor cloned, previ-ously known as VR1, is expressed in a subset ofsmall- to medium-sized nociceptive trigeminalprimary afferent neurons. TRPV1 is sensitive toheat temperature above 43 !C and is also found tobe activated not only by capsaicin and heat butalso by low pH and inflammatory mediator-related molecules, such as products oflipoxygenases, anandamide, and other endo-cannabinoids. Other TRP channels, which areactivated by a distinctive range of temperature,thermo-TRP channels, are also found to beexpressed by TG neurons. While TRPM8 andTRPA1 are activated by cool (<25 !C) and cold(<17 !C) temperature, respectively, TRPV3 andTRPV4 sense a warm range (Tominaga 2007).Given that TRPV1 and TRPA1 are activated bynoxious temperature which produces pain in vivo,

Table 1 Conduction velocity of each type of nerve fiber

Type Erlanger-Gasser classification Diameter (μm) Myelin Conduction velocity (m/s)

Ia Aα 13–20 Yes 80–120Ib Aα 13–20 Yes 80–120II Aβ 6–12 Yes 33–75III Aδ 1–5 Thin 3–30IV C 0.2–1.5 No 0.5–2.0

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they might play important roles in heat- and cold-induced thermal pain. TRPV2 detects the highesttemperature level among the thermo-TRPchannels with a threshold of 52 !C. TRPA1 canbe activated by pungent cysteine-reactivechemicals, such as isothiocyanates (mustard oil),cinnamaldehyde (cinnamon), and allicin (garlic),and also by many endogenous substances that aregenerated at the site of tissue injury and inflam-mation, for example, the highly reactive aldehyde4-hydroxy-2-nonenal (4-HNE), 15-deoxy-12,14-prostaglandin J2, and reactive oxygen and nitro-gen species. The activation of TRPA1 by thesecompounds directly excites nociceptors andthereby generates a warning signal to the organ-ism to protect the body (Chung et al. 2011).

A variety of thermo-TRP channels areexpressed in dental primary afferent neurons(Fig. 1b). Activation of these thermo-TRP chan-nels increases intracellular calcium and evokescationic currents in subsets of neurons, as doesthe appropriate temperature changes (Chung et al.2013). These results suggest that activation ofthermo-TRP channels expressed by dental affer-ent neurons contributes to dental pain evoked bytemperature stimuli. Thermo-TRP channels havethereby been shown to be substantial sensorytransducers that transfer signals elicited by exter-nal noxious thermal stimuli to the nociceptiveneurons (Chung et al. 2013).

Mechanoreceptors responding to mechanicalstress such as direct pressure and tissue deforma-tion are also involved in nociceptive processes inthe trigeminal system. For example, “hydrody-namic theory” describes the cause of dentalpain regarding mechanical forces generated bythe movement of dentinal fluid (Fig. 1c).Low-threshold mechanoreceptors (so-called“algoneurons”) in dental primary afferent nervefibers could be involved in nociception, in con-trast to conventional low-threshold mechanore-ceptors thought to transduce light touch in otherparts of the body (Fried et al. 2011). Piezochannels might be a candidate molecule (Wooet al. 2014).

Further, trigeminal primary afferent neuronsexpress P2X purinoreceptor 3 (P2X3) homomerand P2X2/3 heteromer, a subtype of the P2X

receptor that detects adenosine triphosphate(ATP) released by damaged keratinocytes or ininflammatory sites. Chemical substances are alsosources for nociceptors to transduce pain. Tissueacidosis associated with tissue inflammation orinjury is the representative example. Acid-sensingion channel 3 (ASIC3) and TRPV1 are two majoracid sensors involved in proton-induced hyper-algesic priming (Sun and Chen 2016).

Trigeminal Ganglion

Given that cell bodies of trigeminal primary affer-ent neurons are located in the TG, TG neurons areinvolved in various sensory functions in theorofacial region such as innocuous or noxiousmechanical, thermal, or chemical sensation(Goto et al. 2016). Following application of nox-ious stimuli to the orofacial region, a barrage ofaction potentials is generated in small-diameterprimary afferent neurons, and those are conveyedto the small TG neurons. On the other hand,innocuous stimuli may cause action potentials inlarge-diameter nerve fibers. Various ion channelproteins and neuropeptides are up- and down-regulated following non-noxious and/or noxiousstimuli under physiological conditions (Goto et al.2016). A recent RNA-Seq analysis of TG trans-criptome reveals a comprehensive expression pro-file of all ion channels and G-protein-coupledreceptors (GPCRs) in TG neurons and providesinsight into both trigeminal sensings and the phys-iological and pathophysiological mechanisms ofpain (Manteniotis et al. 2013).

Pathological Changes in TrigeminalGanglion

The trigeminal sensory system represents a dis-tinct and complex functional unit, with its well-characterized nociceptive and modulatory path-ways (Sessle 2000). A range of severe facialpain syndromes, with varying etiologies, are asso-ciated with trigeminal neuropathy. Pain related tonociceptor activation within structures specific tothe orofacial area, such as the tooth pulp and

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cornea, as well as the cranial dura, does not haveclinical correlates in the spinal somatosensorysystem. As such, the treatment regime fortrigeminal-related pains may differ from that ofspinal neuropathic pain (Davies et al. 2010). Thus,changes in TG neurons following peripheral nerveinjury or tissue inflammation are not always com-parable with its counterpart in the spinal somato-sensory system, dorsal root ganglion.

Peripheral nerve injury or orofacial inflamma-tion often causes changes in the excitability of TGneurons, thereby resulting in pain hypersensitiv-ities such as allodynia and hyperalgesia. It is wellknown that excitability and molecular expressionchange in TG neurons under pathological condi-tions. Specifically, differential expression ofvoltage-gated Na+, K+, and Ca2+ channels andhyperpolarization-activated cyclic nucleotide-gated (HCN) channels following trigeminalnerve injury has been shown to contribute to theenhanced excitability of TG neurons. Further,changes in the expression of a variety of mole-cules such as TRPV1 and P2X3 channels in TGneurons are thought to be involved in orofacialsensory dysfunctions associated with trigeminalnerve injury or orofacial inflammation such astemporomandibular joint (TMJ) inflammation.Moreover, the activation of intra-ganglionic com-munication via nitric oxide (NO), nerve growthfactor (NGF), or calcitonin gene-related peptidesignaling plays a major role in the creation andmaintenance of trigeminal pathological pain(Goto et al. 2016).

Satellite glial cells have been shown to beinvolved in orofacial sensory abnormalities asso-ciated with trigeminal nerve injury or orofacialinflammation. It has recently been demonstratedthat neuron-glia interactions such as thoseunderlying a paracrine mechanism via SP-neurokinin 1(NK1) receptor and IL-1β are criticalprocesses involved in the modulation of the excit-ability of TG neurons (Dubner et al. 2014; Gotoet al. 2016). Thus, interactions of TG neurons andsatellite glial cells might play a key role in themanifestation of orofacial sensory dysfunctionssuch as ectopic pain hypersensitivity under path-ological conditions.

Tissue injury or inflammation in masticatorymuscles leads to elevated extracellular excitatoryamino acid concentrations and a high concentra-tion of ATP in the TG. It has recently been dem-onstrated that both ATP- and N-methyl-D-aspartate (NMDA)-induced mechanical hyper-sensitivities involve upregulation and sensitiza-tion of both TRPV1and TRPA1 (Asgar et al.2015). It is possible that TRPV1 and TRPA1function as a downstream integrator of variouspronociceptive/inflammatory intracellular signalsin masticatory muscles (Chung et al. 2011).

Brainstem Nociceptive Neurons

Trigeminal Spinal Nucleus and UpperCervical Spinal Cord

Noxious sensory information in the area inner-vated by the trigeminal nerve is relayed fromtrigeminal afferents to second-order neurons inthe trigeminal sensory nuclear complex (TSNC)in the brainstem and the upper cervical (C1-C2)spinal cord (Jacquin et al. 1986b; Bereiter andBereiter 2000; Sessle 2000) (Figs. 1a and 2a).The TSNC and C1-C2 are the primary sites ofsynaptic integration for sensory inputs from thespecific craniofacial tissues, such as face and oralcavity (Waite and Tracy 1995). The TSNC con-sists of the principal sensory nucleus (PrV) andthe trigeminal spinal nucleus. PrV is a relay stationfor non-noxious sensory information, but not nox-ious information, whereas the trigeminal spinalnucleus (SpV) is an important relay station in thetransmission of orofacial noxious sensory infor-mation, and this nucleus is functionally sub-divided into three nuclei (from rostral to caudal):oralis (Vo), interpolaris (Vi), and Vc (Olszewski1950; Darian-Smith 1973). Since the laminarorganization of neurons in the Vc is similar tothat in the spinal dorsal horn, Vc is also termedthe medullary dorsal horn (MDH) (Gobel 1978).

There is evidence of intrasubnuclar connec-tions between rostral and caudal portions of theTSNC (Ikeda et al. 1984; Jacquin 1986a; Hirataet al. 2003). For example, chemical blockade ofVc has been shown to reduce the excitability of Vo

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neurons responsive to noxious stimulation(Greenwood and Sessle 1976; Chiang et al.2002; Hirata et al. 2003). By contrast, there is areport that GABAA receptor agonist blockade ofneuronal activity of Vi/Vc transition region facil-itates nociceptive neurons of Vc (Hirata et al.2003). Collectively, these findings suggest thatboth ascending and descending connectionswithin the TSNCmay contribute to the integrationof noxious sensory input relevant to orofacialpain (Fig. 2b).

Although it is known that nociceptive Vc neu-rons have similar properties to those at the spinaldorsal horn level, consistent with a prominent rolein nociceptive processing (Dubner and Bennett1983; Bereiter and Bereiter 2000; Sessle 2000),the contribution of the rostral portion of the TSNCto orofacial pain is less precise. Since the majorityof sensory neurons in nociceptive defensive reflex(e.g., nociceptive jaw-opening reflex) are locatedin Vo and this projects to the trigeminal motor

nucleus (Mizuno et al. 1975; Dubner 1978;Sugimoto and Takemura 1993), Vo has a signifi-cant role in the brainstem-central station underlingtrigeminal nociceptive reflexes. Among thesethree nuclei, Vc is the most important relay stationfor trigeminal nociceptive inputs from theorofacial area, as well as the C1-C2 dorsal horn(Dubner et al. 1978; Bereiter and Bereiter 2000).There is considerable evidence suggesting thatVc/C1-C2 junction region differs from the lowerspinal cord. It has also been reported that thenociceptive inputs from receptors in deep cranio-facial tissues are conveyed to the ventral Vi/Vctransition region (Vi/Vc) through the Vc/C1-C2junction region (Bereiter et al. 2002a) (Fig. 2b).These findings suggest that the Vi/Vc transitionzone plays a significant role in deep tissue painprocessing, integrating nociceptive orofacial paininputs, and the development of persistingorofacial pain (Ren and Dubner 2011). Since Vc/C1-C2 neurons have widespread ascending

TSNC

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Fig. 2 Trigeminal sensory nuclear complex and painpathways. (a) Central pain pathway for orofacial areainnervated by the trigeminal nerve. ACC, anterior cingu-late cortex; IC, insular cortex; VPM, posterior ventrome-dial thalamus; PAG, periaqueductal gray; RVM, rostralventral medulla; TSNC, trigeminal sensory nuclear

complex; PrV, principal sensory nucleus; Vo, spinal tri-geminal nucleus oralis; Vi, spinal trigeminal nucleusinterpolaris; Vc, Vo, spinal trigeminal nucleus caudalis;C1-C2, upper cervical dorsal horn. (b) Intrasubnuclar con-nections into the TSNC (Vo, Vi/Vc, Vc, and Vc/C1-C2)and C1-C2 regions

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connections to the hypothalamus, periaqueductalgray (PAG), and other brainstem regions (Keayet al. 1997; Burstein et al. 1998), they can beinvolved in the circuitry control of autonomic out-flow and in endogenous pain modulation circuits(Bossut et al. 1992; Tanimoto et al. 2002).

Over the last several decades, c-Fos expressionand extracellular signal-regulated kinase (ERK)phosphorylation have been known to occur innociceptive neurons in Vc and C1-C2 followingvarious noxious stimuli applied to the orofacialregion (Nomura et al. 2002; Noma et al. 2008;Suzuki et al. 2013). After the excitation of noci-ceptive neurons, these molecules can be detectedin Vc and C1-C2 neurons at 1–2 h for c-Fos in cellnuclei and at less than 5 min for phosphorylatedERK (pERK) in the cytoplasm after noxious stim-uli (Noma et al. 2008). The number of c-Fos orpERK-IR cells is increased following an increasein the stimulus intensity, suggesting that thesemolecules are widely accepted as a reliablemarker of activated neurons following variousnoxious stimuli. Since ERK phosphorylationoccurs at a very early period of fewer than 5 minafter noxious stimuli, pERK-IR cells are thoughtto receive direct inputs from trigeminal nocicep-tive afferents. Further, ERK phosphorylation isblocked byMK801, indicating that NMDA recep-tor mechanism is involved in ERK signaling(Ji et al. 1999).

Nociceptive neurons in the Vc and C1-C2 canbe further classified as “projection neurons” or“local circuit neurons.” Most of the nociceptiveneurons in Vc and C1-C2 regions have beenshown to be local circuit neurons (Okada-Ogawaet al. 2015). Many of these local circuit neuronshave inhibitory functions releasing inhibitorytransmitters, GABA, and glycine (Fig. 3). Theseinhibitory interneurons are thought to be involvedin the modulation of noxious ascending outputsconveying noxious information to the higher cen-tral nervous system. GABA and glycine areknown to bind their receptors, and chloride influxis accelerated, and then membrane potentialsbecome deeper than resting level resulting in areduction of excitability.

Projection neurons have a long axon ascendingto the ventral posterior medial thalamic nucleus(VPM) thalamic nuclei and reticular formation,whereas local circuit interneurons have veryshort axons involved in local “inhibitory” and“excitatory” functions (Sessle 1999, 2000). Noci-ceptive neurons in Vc that project to the VPMoriginate mainly in laminae I and V (Ikeda et al.2003). The majority of projection neurons arefound in rostral Vc rather than caudal Vc/C1-C2junction region and lamina I of Vc projectsheavily to the VPM (Guy et al. 2005). It hasbeen shown that nociceptive Vc and Vo neuronsare markedly inhibited by direct stimulation of thePAG or ventromedial medulla (RVM) (Sessleet al. 1981; Chiang et al. 1989, 1994). However,afferent pathways from second-order Vc neuronsto these endogenous pain control regions are notwell defined.

Compared to the significant inputs from uppercervical levels of the spinal cord to the PAG (Keayet al. 1997), projection from the TSNC to the PAGis sparse (Keay et al. 1997; Beitz 1982). Thesefindings support the idea that laminae I–II of Vcare critical regions processing nociceptive infor-mation relevant for multiple aspects of craniofa-cial pain. Local circuit interneurons have both“inhibitory” and “excitatory” functions. Forexample, in the local inhibitory circuits, there isevidence that local GABAergic mechanisms exerta tonic inhibition of mechanoreceptive transmis-sion in the Vc neurons, and this effect may limitresponsiveness and size of receptive fields of theVc neurons (Takeda et al. 2000).

The trigeminal afferents terminate soma-totopically in Vc, with mandibular afferentsending dorsally and ophthalmic afferents ven-trally in Vc; mandibular endings becomemore dorsomedial and ophthalmic endingsmore ventral (Waite and Tracy 1995) (Fig. 4a).At the caudal level of TSNC, craniofacial tissuesare represented in a series of semicircular bandsthat converge at the rostral midline of the faceand by medial-lateral arrangement in which thehead is inverted (Jacquin 1986; Shigenaga et al.1986).

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Physiology of Trigeminal NociceptiveNeurons

Orofacial noxious information is conveyed to thehigher CNS regions via Vc and C1-C2 neurons.As shown in Fig. 4b, there are two types of noci-ceptive neurons classified as nociceptive-specific(NS) neurons (superficial laminae I-II) and WDRneurons (both in superficial and deep laminae I–IIand IV–V) in the SpVc and C1-C2 based on theirsensitivity to mechanical stimulation applied toorofacial areas such as facial skin (Sessle 1999).NS neurons respond only to noxious stimulation(e.g., high-threshold mechanical stimulation) ofthe receptive field, suggesting that NS neuronsencode stimulus localization (Sessle 1999).

WDR neurons respond to both noxious (via Aδ-and C-fibers) and non-noxious (via Aβ-fiber)stimulations and have large receptive fields(Iwata et al. 2001; Takeda et al. 2011) (Fig. 2a).Graded noxious stimuli applied to the most sensi-tive area of the receptive field produce increasedfiring frequency of Vc WDR neurons in propor-tion to stimulus intensity, and many of them alsorespond to noxious heat stimulation (Fig. 4b, c),suggesting that WDR neurons encode stimulusintensity. The Vc and C1-C2 NS and WDR neu-rons also commonly receive convergent inputsfrom tooth pulp, facial skin, jaw, masseter muscle,and phrenic afferents (Razook et al. 1995; Sessleet al. 1986; Takeda et al. 2005). Thus they likelycontribute to the phenomenon of referred pain,

Glu

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Fig. 3 Schematic diagram of the synaptic transmissionof nociceptive neurons in Vc and C1-C2. Three types ofnociceptive neurons exist in Vc and C1-C2, projectionneuron, and inhibitory and excitatory interneurons. Eachneuron is connected to each other with excitatory or inhib-itory synapses. Glu, glutamate; SP, substance P; ERK,

extracellular signal-regulated kinase; NK1-R, neurokinin1; NMDA-R, N-methyl-D-aspartic acid receptor; AMPA-R, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid receptor; GABA, gamma-aminobutyric acid; Nav,voltage-gated sodium channel

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whereby pain is associated with an injury affect-ing a visceral tissue. Further, the mechanicalthreshold in the center of the receptive field islow and that in the surrounding portion of thatarea is high (Iwata et al. 2002).

Neurotransmitters in BrainstemNociceptive Neurons

Using immunohistochemistry and in situ hybridi-zation histochemical studies has revealed that avariety of classical neurotransmitter substancesand their receptors are associated with the subsetsof trigeminal primary afferent neurons (Lazarov2012). Among them are amino acids, glutamicacid (Glu), γ-aminobutyric acid (GABA), gly-cine) and monoamines (noradrenaline, dopamine,

and serotonin (5-HT)), acetylcholine (Ach), andadenosine triphosphate (ATP).

After the activation of nociceptive Aδ- andC-terminals associated with external noxiousstimulation, nerve impulses are conducted to thecentral terminals and depolarize them which sub-sequently triggers the release of classical neuro-transmitters. Neuroanatomical and molecularcharacterization of nociceptors has revealed fur-ther heterogeneity, particularly in C-fibers (Sniderand McMahon 1998). For example, the pepti-dergic population of C nociceptors releases theneuropeptides substance P (SP) and calcitoningene-related peptides (CGRP); they also expressthe tyrosine kinase A (trkA) neurotrophin receptorwhich responds to NGF. The non-peptidergicpopulation of C nociceptors expresses c-retneurotrophic receptor that is targeted by a glial-

NS neuron

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Fig. 4 General characteristics of trigeminal nocicep-tive-specific (NS) and wide dynamic range (WDR) neu-rons. (a) Connections between nociceptive andnon-nociceptive trigeminal primary afferent fibers andlayers (I–V) of spinal trigeminal nucleus caudalis.

V1, V2, and V3 indicate ophthalmic, maxillary, and man-dibular nerves, respectively. (b) A typical example of dis-charge patterns in NS and WDR neurons responding tomechanical stimulation of receptive fields. (c) Stimulus-response function for NS and WDR neurons

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derived neurotrophic factor, as well as neurturinand artemin.

Pathological Changes in BrainstemNociceptive Neurons

Peripheral tissue injury and inflammation can alterthe properties of somatic sensory pathways,resulting in behavioral hypersensitivity and paincaused by both noxious stimuli (hyperalgesia) andnormally innocuous stimuli (allodynia) (Scholzand Woolf 2002) (Fig. 5a). Thus, it can be

assumed that peripheral sensitization couldtrigger central sensitization, leading to chronicpathological pain states. Peripheral inflammationand/or injury activate intracellular signaling trans-duction pathways in nociceptor terminals andreduction of activation threshold and an increasein firing frequency of action potentials (Garry andHargreaves 1992; Bereiter and Benetti 1996;Scholz and Woolf 2002). High-frequencyimpulses conduct to central terminals of primaryafferents can induce neurotransmitter release andincrease the excitability of second-order neuronsvia upregulation of postsynaptic receptors in Vc

Pain

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Fig. 5 Themechanism underlying central sensitizationand pathological pain. (a) Following inflammation andtissue injury of an area innervated by trigeminal nerves,large peripheral sensitization can trigger central sensitiza-tion, leading to chronic pathological pain states. (b) Themechanism of central sensitization depends on the followingthree postulated mechanisms: (1) increase in the excitatorymechanism, (2) loss of inhibitory mechanism, and (3) glial-neuronal interaction. Following inflammation and tissue

injury, increased firing impulses conducted through Aδ-/C-fibers in the central terminals, then increase in excitatorymechanism and lose inhibition via glial-neuronal interactionevoked by augmented nociceptive signal information. Theseaugmented nociceptive signals are associated with the pri-mary symptom of pathological pain. (c) The main symptomof pathological pain: spontaneous pain caused by no stimu-lus. Abnormality caused by both noxious stimuli (hyper-algesia) and normally innocuous stimuli (allodynia)

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and C1-C2. Consequently, sensitization of Vc andC1-C2 neurons may contribute to inflammation-induced “spontaneous pain,” “hyperalgesia,” and“allodynia.” The mechanism of central sensitiza-tion depends on the following three postulatedmechanisms: (1) increase in the excitatory mech-anisms, (2) loss of inhibitory mechanisms, and(3) glial-neuronal interaction (Fig. 5b).

Under normal conditions, acute pain is sig-naled by the release of excitatory neurotransmit-ters such as glutamate from the central terminalsof nociceptive afferents, generating excitatorypostsynaptic potentials (EPSPs) in the second-order neurons. EPSPs occur primarily throughactivation of postsynaptic AMPA ionotropic glu-tamate receptors. Summation of subthresholdEPSPs in the postsynaptic neurons eventuallyresults in the firing of neuronal action potentialsand transmission of the signals to higher-orderneurons. Under these conditions, NMDA gluta-mate receptor is silent. Following persistent injuryand inflammation, activated Aδ- and C-fibersrelease a variety of neurotransmitters [glutamate,SP, CGRP, brain-derived neurotrophic factor(BDNF), and ATP], and these transmitters act onreceptors of second-order neurons. As a conse-quence, increased release of neurotransmittersfrom nociceptive afferents will sufficiently depo-larize postsynaptic nociceptive neurons to activatenormally silent NMDA glutamate receptors. Thenociceptive neurons can signal, increase intracel-lular calcium, and activate Ca2+-dependent signal-ing pathways and second messengers includingmitogen-activated protein kinase (MAPK), pro-tein kinase C (PKC), and protein kinase A(PKA). This cascade of events can strengthensynaptic transmission (neoplastic changes) andincrease the excitability of nociceptive neuronsand facilitate the nociceptive transmission tohigher CNS regions (Basbaum et al. 2009)(Fig. 5b, c).

GABAergic and glycinergic inhibitory inter-neurons are densely distributed in the superficialspinal dorsal horn and Vc which postulates thatloss of function of these inhibitory interneuronswould result in increased pain (Merzack and Wall1965). Under normal conditions, inhibitory inter-neurons continuously release GABA and/or

glycine to decrease the excitability of nociceptiveneurons or interneurons in Vc and modulate noci-ceptive transmission (inhibitory tone) (Basbaumet al. 2009; Malan et al. 2002; Sivilotti and Woolf1994; Yaksh 1965; Takeda et al. 2000). In thesetting of persistent injury and inflammation, thisinhibition can be lost (disinhibition), resulting inhyperalgesia. Also, disinhibition can enablenon-nociceptive myelinated Aβ-primary afferentsto engage the nociceptive transmission circuitrysuch that normally non-noxious stimuli are nowperceived as painful. Combined with NMDA-mediated central sensitization, disinhibitionenhances spinal cord outputs in response to pain-ful and non-painful stimulation, contributing tomechanical allodynia (Keller et al. 2007; Torsneyand MacDermott 2006) (Fig. 5b, c).

A huge number of glial cells, microglia,astroglia and oligodendroglia are known to bedistributed in the whole brain and have significantfunctions involved in nutrition, structure mainte-nance, and phagocytosis. Glial cells are thought tobe involved in the modulation of neuronal activityby releasing various molecules such as glutamate,glutamine, neurotrophic factors, and cytokinesfollowing activation and also known to expressvarious receptors involved in the modulation ofexcitabilities of nociceptive neurons receivingorofacial noxious inputs (Chiang et al. 2011;Iwata et al. 2011).

Recent studies have reported that microglialcells are involved in the modulation of neuronalexcitability as well as nourishing and supportingCNS structures (Cao and Zhang 2008; Milliganand Watkins 2009). Two types of glial cells(microglia and astroglia) are known to be hyper-active in the spinal dorsal horn following nerveinjury and inflammatory conditions (Cao andZhang 2008; Milligan and Watkins 2009). Undernormal circumstances, the microglia function asresident macrophages of the CNS. Persistentinjury and inflammation can promote the releaseof ATP and chemokine and fractalkine from theprimary afferent terminals that stimulate micro-glial cells. In particular, activation of purinergic,fractalkine, and Toll-like receptors on microgliaresults in the release of BDNF which, throughactivation of trkB receptors expressed in the

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nociceptive neurons, promotes increased excit-ability and enhanced pain in response tonon-noxious and noxious stimulation (hyper-algesia and allodynia). Activated microglia alsorelease a host of cytokines, such as tumor necrosisfactor α (TNFα), interleukin-1β (IL-1β), and otherfactors that contribute to central sensitization. Onthe other hand, astroglial cells may also becomehyperactive and release glutamine which is takenup at presynaptic terminals via glutamine trans-porter, resulting in an increase in glutamaterelease from the presynaptic terminals and caus-ing an enhancement of Vc and C1-C2 neuronalexcitability (Chiang et al. 2007; Okada-Ogawaet al. 2009). Therefore, astroglial cell activationin the Vc and C1-C2 may also contribute to cen-tral sensitization of nociceptive Vc and C1-C2neurons, resulting in orofacial hyperalgesia orallodynia following nerve injury and inflamma-tion (Fig. 5b, c).

Higher Brain Function RegulatingOrofacial Nociception

Ascending Orofacial Pain Pathways

Projection neurons in the Vc and C1-C2 areknown to send their axons to the thalamic nuclei(VPM and medial thalamic nuclei) and PBN(Iwata et al. 1992, 1998, 2011) (Fig. 6). Recentanatomical studies have demonstrated that pro-jections from the Vc and C1-C2 to the PBN aremuch denser compared with those to the VPM andmedial thalamic nuclei (Al-Khater and Todd2009; Akiyama et al. 2016). Nociceptive neuronsreceiving noxious inputs from the orofacial regionare somatotopically organized within the VPMbut not in the medial thalamic nuclei and PBN.Intraoral noxious information is conveyed to thesomatosensory cortex via the medial portion ofthe VPM and face and head via the lateral portionof the VPM (Willis et al. 2001). Nociceptive neu-rons in the VPM receiving inputs from theorofacial region send axons to the primary (SI)and secondary (SII) somatosensory cortical neu-rons whereas those of medial thalamic nuclei andPBN project to the limbic cortices such as anterior

cingulate cortex (ACC) and insula cortex (Ins).Some previous studies have documented the elec-trophysiological characteristics of nociceptiveneurons in the SI, SII, ACC, and Ins, and thosein SI and SII are classified as WDR and NSneurons, and ACC neurons are NS and noxious-tap neurons (Vogt 2005). Ins neurons are known toreceive autonomic inputs (sympathetic and para-sympathetic) and are involved in the modulationof autonomic responses, but there is no dataregarding response properties of Ins nociceptiveneurons (Ito 1998). Although it is evident thatthese cortical areas are involved in pain, thedetails of the involvement of these higher brainregions in pain are still largely unknown.

Sensory-Discriminativeand Motivational and Affective Aspectsof Pain

Pain is known to have very complicated aspects;sensory-discriminative and motivational andaffective aspects (Dubner 1988). The sensory-discriminative aspect of pain is analogous tonon-noxious touch sensation and is thought to beinvolved in the discrimination of pain featuressuch as its location, intensity, and quality. Thissensory function is critical for survival. For exam-ple, when we receive a needle insertion into thefinger, we can detect the location, intensity, andquality of the pain immediately after the injury.This sensory-discriminative aspect is necessaryfor humans to survive. SI and SII are thought tobe involved in this aspect. On the other hand, themotivational and affective aspects of pain arebelieved to be related to emotional and autonomicresponses due to long-lasting, intense noxious stim-uli. This aspect is considered to be a feature ofpersistent pain associated, for example, withchronic inflammation or peripheral nerve injury. Inthis type of pain, it is often difficult to discriminatethe localization, intensity, and quality of the pain.

Another important issue is the prediction, cog-nition, and attention of pain. Nociceptive neuronsin the ACC may be activated before a noxiousstimulus is applied or when the subject predictsthe noxious stimulus, indicating that nociceptive

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neurons in the ACC are involved in pain predic-tion. Some of the nociceptive neurons alsodecrease their activity when attention is movedto a different modality of stimuli such as light orsound, suggesting that these nociceptive neuronsare involved in attention to the noxious stimuli(Koyama et al. 1998; Iwata et al. 2005). Paincognition is also important, but there is no animaldata regarding this aspect. It may be possible toget new insight regarding brain function involvedin pain cognition by human functional MRI(fMRI) studies (Davis and Stohler 2014).

Human Brain Function for OrofacialPain Sensation

Various strategies to analyze human brain func-tion have been dramatically developed in recentdecades. fMRI is considered a useful tool to dis-cover brain areas involved in pain in humans. Thethalamus, brainstem, SI and SII, ACC, and Ins inhumans are activated following painful stimuli,and these regions are thought to be involved inpain perception (Davis and Stohler 2014; Vachon-Presseau et al. 2016). The SI region is stronglyactivated by hypnotic suggestions that pain

intensity is increased without any noxious stimuli,whereas ACC area is activated by suggestions thatemotion is enhanced (Rainville et al. 1999). In ahuman magnetoencephalography study,SI-evoked responses following painful stimulihave shorter latencies and smaller amplitudescompared with ACC, suggesting that ACC mayhave a larger contribution to pain perception com-pared with SI (Nakata et al. 2008). It is highlylikely that SI is involved in the coding of painintensity, and ACC and Ins are involved in moti-vational and affective aspects of pain. These func-tional relationships of SI, ACC, and Ins to painperception are consistent with results from variousanimal studies. Some of the fMRI studies havereported that the prefrontal cortex (PFC) is alsoactivated by painful stimulation of the hand inhumans (Nakata et al. 2008). It has not beenevaluated if PFC neurons receive noxious inputsfrom the orofacial area in animal studies becausemost of the animal studies have been conductedunder anesthesia. At present, although manypapers have been published regarding orofacialpain structures in the human brain, the detailedmechanisms underlying orofacial pain in humansare not entirely understood (Nash et al. 2009;Moayedi et al. 2011; Davis and Stohler 2014).

Trigeminothalamicpathway

mid-line

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oralisinterpolariscaudalis (Vc)

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Lateral systemMedial system

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VPM

Fig. 6 Two distinctascending pathways,medial and lateral systemsin orofacial painperception. Orofacialnoxious inputs areconveyed to Vc and C1-C2,and further relayed tosomatosensory (SI-SII) andlimbic cortices (ACC andIns) via thalamic nuclei,VPM, and medial thalamicnuclei, respectively. VPM,ventral posteromedialthalamic nucleus; SI,primary somatosensorycortex; SII, secondarysomatosensory cortex;ACC, anterior cingulatecortex; Ins, insular cortex

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Descending Modulationof Orofacial Pain

Descending Pathways InfluencingOrofacial Pain

The ascending pathway in the CNS related toorofacial pain consists of many complex neuronalstructures. Firstly, as noted above, nociceptorswhich exist in the free nerve endings of primaryafferent Aδ- and C-fibers respond to mechanical,thermal, or chemical noxious stimulation of theorofacial region, e.g., orofacial skin, oralmucosa, dental pulp, periodontal tissue, orTMJ. The noxious information is then conductedto the medulla where the central terminals of theAδ- and C-fibers release a number of excitatoryneurotransmitters, and nociceptive neuronsare excited. These events initiate the central neu-ral processing of nociceptive information to thecortical and limbic circuits for the sensory per-ception that is transmitted by way of severalnuclei in the brainstem and the thalamic nuclei(Sessle 2011). The ascending noxious informa-tion can, however, be modulated by thedescending pain modulation system through var-ious mechanisms.

Potent drugs clinically used for pain reliefinclude the opioid family which is representedby morphine. Indeed, morphine microinjectioninto the PAG, RVM, amygdala, or anterior insularcortex produces an intensive analgesic effect(Yaksh and Rudy 1978). At present, three classi-cal receptors (μ-, δ-, and κ-opioid receptors) and afourth related receptor (opioid receptor-like(ORL1) receptor) have been identified as opioidreceptors which are widely distributed in the brainsuch as PAG, RVM, and dorsolateral pontomesen-cephalic tegmentum (DLPT) and superficial lam-inae of the spinal dorsal horn (Mansour et al.1995; Darland et al. 1998). Opioid receptorsbelong to members of the G-protein-coupledreceptors (GPCRs). Moreover, the major classesof endogenous opioid peptides, β-endorphin,enkephalin, and the dynorphin, bind the aboveopioid receptors present in the CNS. These opioidpeptides are derived from a large, usually inactive

protein precursor. For instance, β-endorphin iscleaved from pro-opiomelanocortin which is syn-thesized from adrenocorticotrophic hormone ormelanocyte-stimulating hormone. Though thevarious types of opioid receptors are distributedwidely within the CNS and peripheral nervoussystem, the affinity for opioid receptors shows acharacteristic pattern due to the types of opioidpeptides. Enkephalin is the dominant ligand forδ-opioid receptors compared to μ-opioid recep-tors; β-endorphin has equal affinity for δ-opioidreceptors and μ-opioid receptors and low affinityfor κ-opioid receptors. Dynorphin has a highaffinity for κ-opioid receptors. The opioid pep-tides signaling via various opioid receptors in thebrain and spinal cord induce hyperpolarizationand inhibition of spike activity in neurons byblocking neurotransmitter release through inhibi-tion of calcium influx into the presynaptic termi-nal or opening potassium channels, resulting inthe depression of neuronal activity (Nagi andPineyro 2014; Ossipov et al. 2014).

The midbrain PAG and RVM play a significantrole in the major pain-modulating pathway (Lauand Vaughan 2014). Information from the frontallobe or amygdala is conveyed via the hypothala-mus to the PAG. In turn, neurons in the PAGcommunicate with serotonergic and non-serotonergic projection neurons in the RVM andalso interact with noradrenergic projection neu-rons in the DLPT. These projection neurons mod-ulate the excitability of Vc nociceptive neuronswhich carry nociceptive signals to higher levels ofthe CNS. Opioid signaling leads to changes in theexcitability of these neurons, resulting in theenhancement of descending pain suppression.The μ-opioid or δ-opioid receptors are also abun-dant in primary nociceptive neurons (Minamiet al. 1995; Brederson and Honda 2015).Intraplantar administration of morphine which isa μ-opioid receptor agonist exerts anti-hyperalgesic effects in a rat model of diabeticpolyneuropathy (Schiene et al. 2015). Theseresults indicate that the opioid signaling in pri-mary nociceptive neurons via opioid receptors isinvolved in peripheral analgesia (Bakke et al.1998; Stein and Zollner 2009).

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Modulation of Trigeminal NociceptiveNeurons

5-HT-containing neurons in RVM project to theVc and C1-C2. Depending on the 5-HT receptorsubtype, 5-HT in the Vc and C1-C2 acts as eitherinhibitor or facilitator (Suzuki et al. 2004; Dogrulet al. 2009), e.g., 5-HT2A, 5-HT3, and 5-HT4 areexcitatory 5-HT receptors and 5-HT1A, 5-HT1B,and 5-HT1C are inhibitory 5-HT receptorsexpressed in the central terminals of nociceptiveprimary afferents. Therefore, 5-HT released from5-HT-containing neurons can change the excit-ability of nociceptive neurons in the Vc andC1-C2. 5-HT1B is expressed in primary afferents,and the activation of presynaptic 5-HT1B reducesglutamate release from primary afferent terminalsin the Vc and C1-C2, resulting in modulation ofnociceptive neuronal activity (Choi et al. 2012).Furthermore, by acting on 5-HT1A which areinhibitory receptors expressed in second-orderneurons, 5-HT exerts the suppressive effect onnociceptive neurons. 5-HT7, an excitatory 5-HTreceptor, has also been identified in GABAergicinterneurons in the Vc and C1-C2, as well as oncentral terminals of nociceptive primary afferents(Doly et al. 2005). The excitation of 5-HT7enhances the release of GABA, resulting indepression of the excitability of secondary noci-ceptive neurons (Brenchat et al. 2009).

The A5 (locus coeruleus), A6, and A7(Kölliker-Fuse) noradrenergic nuclei are majorsources of direct noradrenergic projections tomedullary and spinal dorsal horns (Willis 1985;Holden and Proudfit 1998; Bajic and Proudfit1999). Noradrenaline (NA) released from themedullary and spinal terminals and of these nor-adrenergic neurons plays a role in inhibition of thepresynaptic and postsynaptic nociceptive trans-mission. Many previous studies have shown thatNA signaling exerts a potent antinociceptiveeffect mediated by the activation of α2 receptors(Pertovaara 2006). Noradrenergic systems inhibitnociceptive transmission at the level of themedulla and spinal cord through presynapticmechanisms. Released NA activates α2-adrener-gic receptors expressed in the central terminal of

nociceptive primary afferents, inhibiting releaseof excitatory neurotransmitters such as glutamatefrom the primary afferent terminals. Moreover,postsynaptic sites of second-order nociceptiveneurons also express α2-adrenergic receptors;NA signaling induces a potent antinociceptiveeffect by acting on these α2-adrenergic receptors.Further, α1-adrenergic receptors in GABA inter-neurons produce depolarization, which results inthe attenuation of the hyperexcitability of second-order nociceptive neurons that occurs under path-ological conditions.

In this manner, the summation of 5-HT, NA,and GABA signaling in second-order nociceptiveneurons in Vc and C1-C2 results in thesedescending systems acting as inhibitor or facilita-tor (Fig. 7). Although the precise medullary andspinal mechanisms involved in descending path-ways modulating orofacial pain remain unclear,these descending systems work almost invariablyas an inhibitor.

Pathological Changesin the Descending System

The descending pain inhibitory system canbecome dysfunctional in patients with a chronicpain condition (e.g., temporomandibular disor-ders), resulting in enhanced sensitivity to noxiousstimuli (King et al. 2009). Recent studies havedemonstrated that the descending inhibitory orfacilitatory systems are modulated in experimen-tal chronic pain models (Burgess et al. 2002;Dubner et al. 2014; Rahman et al. 2009; Weiet al. 2010). Orofacial neuropathic pain inducedby infraorbital nerve injury or stress-induced TMJpain is primarily dependent on the central mech-anisms involving 5-HT derived from the RVMand activation of 5-HT3 receptors in the Vi/Vc(Okubo et al. 2013; Okamoto et al. 2015). Clinicalstudies have indicated that 5-HT3 receptor antag-onist administration is useful for the treatment ofneuropathic pain associated with fibromyalgia(Seidel and Muller 2011; Forster and Baron2012). In human studies, μ-opioid receptor avail-ability in the nucleus accumbens (which is an area

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involved in pain modulation) is reduced in trigem-inal neuropathic pain (DosSantos et al. 2012).While dysfunction of the descending pain inhibi-tory system in orofacial pain patients is notentirely understood, increased knowledge of thedysfunctional modality of descending pain inhib-itory system offers approaches to developimproved orofacial pain therapy.

Conclusion and Future Directions

Peripheral and central mechanisms, ascendingand descending pathways related to orofacialpain and its neuromodulation, and the pathogene-sis of persistent orofacial pain have been reviewedand discussed in this chapter. Many of the trigem-inal nerve fibers respond to cool or cold as well asheat and mechanical stimuli applied to theintraoral mucous membrane. A barrage of action

potentials following noxious stimulation of theorofacial regions are conveyed to the Vc andC1-C2, and those are further relayed to thesomatosensory or limbic cortices via medial andlateral thalamic pathways. Pain threshold is sig-nificantly lower in the orofacial regions comparedwith other body parts. Further, orofacial noxiousinputs are represented by the widest areas in theVPM and somatosensory cortex, indicating thatneurons receiving noxious inputs from theorofacial regions are distributed more denselyand broadly than in other body parts.

Under pathological conditions such as trigem-inal nerve injury or orofacial inflammation, painintensity becomes much stronger than that ofother body parts. Persistent orofacial pain alsocauses a variety of deficits in the orofacial motorand sensory functions such as mastication,swallowing, and taste. It is crucial to know theunderlying mechanism of pathological orofacial

Serotonergic

Vc

PAG

Central nucleus of the amygdala

RVMLC

Noradrenergic neuron

Secondary neuronPrimary neurona 2

5-HT1A

Noradrenergic neuronSerotonergic neuron

neuron

Fig. 7 Descending pathways involved in pain modula-tion. Descending pain modulation is mediated throughprojections to the periaqueductal gray (PAG), which alsoreceives inputs from other sites, including the hypothala-mus. PAG communicates with the rostroventromedialmedulla (RVM) that sends descending projections to the

trigeminal spinal subnucleus caudalis (Vc). The noradren-ergic locus coeruleus (LC) receives inputs from the PAGand sends descending noradrenergic inhibitory projectionsto Vc. The effect of 5-HTand noradrenaline in Vc canworkas either inhibitor or facilitator, depending on its receptorsubtype

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pain to improve the quality of life of orofacial painpatients. Satellite cell activation in TG, astrocyte,and microglial cell activation in Vc and C1-C2can occur following trigeminal nerve injury ororofacial inflammation. Neuron-glia interactionsare thought to be a key mechanism in the devel-opment of persistent orofacial pain associatedwith trigeminal injury or orofacial inflammation;however, the detailed mechanisms underlying thepathogenesis of persistent orofacial pain are stillunknown. Further studies are necessary to revealthese underlying mechanisms of persistentorofacial pain associated with trigeminal nerveinjury or orofacial inflammation so that new orimproved diagnostic and treatment approachescan be applied in the management of patientswith persistent orofacial pain.

References

Akiyama T, Curtis E, Nguyen T, Carstens MI, Carstens E.Anatomical evidence of pruriceptive tri-geminothalamic and trigeminoparabrachial projectionneurons in mice. J Comp Neurol. 2016;524:244–56.

Al-Khater KM, Todd AJ. Collateral projections of neuronsin laminae I, III, and IVof rat spinal cord to thalamus,periaqueductal gray matter, and lateral parabrachialarea. J Comp Neurol. 2009;515:629–46.

Asgar J, Zhang Y, Saloman JL, Wang S, Chung MK,Ro JY. The role of TRPA1 in muscle pain and mechan-ical hypersensitivity under inflammatory conditions inrats. Neuroscience. 2015;310:206–15.

Bajic D, Proudfit HK. Projections of neurons in the peri-aqueductal gray to pontine and medullary catechol-amine cell groups involved in the modulation ofnociception. J Comp Neurol. 1999;405(3):359–79.

Bakke M, Hu JW, Sessle BJ. Morphine application toperipheral tissues modulates nociceptive jaw reflex.Neuroreport. 1998;9(14):3315–9.

Basbaum AI, Bautista DM, Scherrer G, Jullius D. Cellularand molecular mechanisms of pain. Cell. 2009;139:267–84.

Beitz AJ. The organization of afferent projections to themidbrain periaqueductal gray of the rat. Neuroscience.1982;7:133–59.

Benarroch EE. Pain-autonomic interactions: a selectivereview. Clin Auton Res. 2001;11:343–9.

Bereiter DA, Benetti AP. Excitatory amino acid releasewithin spinal trigeminal nucleus after mustard oil injec-tion into the temporomandibular joint region of the rat.Pain. 1996;67:451–9.

Bereiter DA, Bereiter DF. Morphine and NMDA receptorantagonism reduce c-Fos expression in spinal

trigeminal nucleus produced by acute injury to theTMJ region. Pain. 2000;85:65–77.

Bereiter DA, Bereiter DF, Ramos M. Vagotomy preventsmorphine-induced reduction in Fos-like immunoreac-tivity in trigeminal spinal nucleus produced after TMJinjury in a sex-dependent manner. Pain. 2002a;96(1–2):205–13.

Bereiter DA, Shen S, Benetti AP. Sex differences in aminoacid release from rostral trigeminal subnucleus caudalisafter acute injury to the TMJ region. Pain.2002b;98:89–99.

Bossut DF, Whitsel EA, Maixner W. A parametric analysisof the effects of cardiopulmonary vagal electro-stimulation on the digastric reflex in cats. Brain Res.1992;579(2):253–60.

Brederson JD, Honda CN. Primary afferent neuronsexpress functional delta opioid receptors in inflamedskin. Brain Res. 2015;1614:105–11.

Brenchat A, Romero L, Garcia M, Pujol M, Burgueno J,Torrens A, et al. 5-HT7 receptor activation inhibitsmechanical hypersensitivity secondary to capsaicinsensitization in mice. Pain. 2009;141(3):239–47.

Burgess SE, Gardell LR, Ossipov MH, Malan Jr TP,Vanderah TW, Lai J, et al. Time-dependent descendingfacilitation from the rostral ventromedial medullamaintains, but does not initiate, neuropathic pain.J Neurosci. 2002;22(12):5129–36.

Burstein R, Yamamura H, Malick A, Strassman AM.Chemical stimulation of the intracranial dura inducesenhanced responses to facial stimulation in brainstemtrigeminal neurons. J Neurophysiol. 1998;79:964–82.

Cao H, Zhang YQ. Spinal glial activation contributes topathological pain states. Neurosci Biobehav Rev.2008;32:972–83.

Chiang CY, Hu JW, Dostrovsky JO, Sessle BJ. Change inmechanoreceptive properties of somatosensory brainstem neurons induced by stimulation of nucleus raphemagnus in cats. Brain Res. 1989;485:371–81.

Chiang CY, Hu JW, Dostrovsky JO, Sessle BJ. Para-brachial area and nucleus raphe magnus-induced mod-ulation of nociceptive trigeminal subnucleus caudalisneurons activated by cutaneous and deep inputs.J Neurophysiol. 1994;71:2430–45.

Chiang CY, Hu JW, Dostrovsky JO, Sessle BJ. Centralsensitization of nociceptive neruons in trigeminal sub-nucleus oralis depends on the integrity of subnucleuscaudalis. J Neurophysiol. 2002;88:256–64.

Chiang CY, Wang J, Xie YF, Zhang S, Hu JW, DostrovskyJO, Sessle BJ. Astroglial glutamate-glutamine shuttle isinvolved in central sensitization of nociceptive neuron inrat medullary dorsal horn. J Neurosci. 2007; 27:9068–76.

Chiang CY, Dostrovsky JO, Iwata K, Sessle BJ. Role ofglia in orofacial pain. Neuroscientist. 2011;17:303–20.

Choi IS, Cho JH, An CH, Jung JK, Hur YK, Choi JK, et al.5-HT(1B) receptors inhibit glutamate release from pri-mary afferent terminals in rat medullary dorsal hornneurons. Br J Pharmacol. 2012;167(2):356–67.

Chung MK, Jung SJ, Oh SB. Role of TRP channels in painsensation. Adv Exp Med Biol. 2011;704:615–36.

Neurophysiology of Orofacial Pain 19

Page 20: Neurophysiology of Orofacial Pain - Berandafkg.usu.ac.id/images/Bahan_Kuliah/Buku_McCullough/... · Neurophysiology of Orofacial Pain Koichi Iwata, Mamoru Takeda, Seog Bae Oh, and

Chung G, Jung SJ, Oh SB. Cellular and molecular mech-anisms of dental nociception. J Dent Res. 2013;92(11):948–55.

Darian-Smith I. The trigeminal system. In: Iggo A, editor.Handbook of sensory physiology, vol. 2, somatosen-sory system. Berlin: Springer; 1973. p. 271–314.

Darland T, Heinricher MM, Grandy DK. OrphaninFQ/nociceptin: a role in pain and analgesia, but somuch more. Trends Neurosci. 1998;21(5):215–21.

Davies AJ, Kim YH, Oh SB. Painful neuron-microgliainteractions in the trigeminal sensory system. OpenPain J. 2010;3:14–28.

Davis KD, Stohler CS. In: Sessle BJ, editor. Orofacial pain:recent advances in assessment, management, andunderstanding of mechanisms. Washington, DC: IASPPress; 2014. p. 165–83.

Dogrul A, Ossipov MH, Porreca F. Differential mediationof descending pain facilitation and inhibition by spinal5HT-3 and 5HT-7 receptors. Brain Res. 2009;1280:52–9.

Doly S, Fischer J, Brisorgueil MJ, Verge D, Conrath M.Pre- and postsynaptic localization of the 5-HT7 recep-tor in rat dorsal spinal cord: immunocytochemical evi-dence. J Comp Neurol. 2005;490(3):256–69.

DosSantos MF, Martikainen IK, Nascimento TD, Love TM,DeboerMD,Maslowski EC, et al. Reduced basal gangliamu-opioid receptor availability in trigeminal neuropathicpain: a pilot study. Mol Pain. 2012;8:74.

Dubner R. Neurophysiology of pain. Dent Clin NAm. 1978;22(1):11–30.

Dubner R. The effect of behavioral state on the sensoryprocessing of nociceptive and non-nociceptive infor-mation. Prog Brain Res. 1988;77:213–28.

Dubner R, Bennett GJ. Spinal and trigeminal mechanismof nociception. Annu Rev Neurosci. 1983;6:381–418.

Dubner R, Sessle BJ, Story AT. Jaw and tongue reflex. In:Dubner R, Sessle BJ, Story AT, editors. The neuralbasis of orofacial function. New York: Plenum; 1978.p. 246–310.

Dubner R, Iwata K, Wei F. In: Sessle BJ, editor. Orofacialpain: recent advances in assessment, management, andunderstanding of mechanisms. Washington, DC: IASPPress; 2014. p. 331–50.

Forster M, Baron R. One failed clinical trial (of 5HT3antagonists) does not invalidate the concept. Pain.2012;153(2):263–4.

Fried K, Sessle BJ, Devor M. The paradox of pain fromtooth pulp: low-threshold “algoneurons”? Pain.2011;152(12):2685–9.

Garry MG, Hargreaves KM. Enhanced release of immuno-reactive CGRP and substance P from spinal dorsal hornslices occurs during carrageenan inflammation. BrainRes. 1992;582:239–142.

Gobel S. Golgi studies of the neurons in layer II of thedorsal horn of the medulla (trigeminal nucleuscaudalis). J Comp Neurol. 1978;180:395–413.

Goto T, Oh SB, Takeda M, Shinoda M, Sato T,Gunjikake KK, et al. Recent advances in basic researchon the trigeminal ganglion. J Physiol Sci. 2016;66:381.

Greenwood LF, Sessle BJ. Input to trigeminal brainstemneurons from facial, oral, tooth and paharygolarygealtissue: II role of trigeminal nucleus caudalis in modu-lating responses to innocuous and noxious stimuli.Brain Res. 1976;117:227–38.

Guy N, Chalus M, Dallel R, Voisin DL. Both oral andcaudal parts of the spinal trigeminal nucleus project tothe somatosensory thalamus in the rat. Eur J Neurosci.2005;21:741–54.

Haley JE, Dickenson AH. Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chem-ical nociception in the rat. Brain Res.2016;518:218–26.

Hirata H, Okamoto K, Bereiter DA. GABAA receptoractivation modulates corneal unit activity in rostraland caudal portions of trigeminal subnucleus caudalis.J Neurophysiol. 2003;90:2837–49.

Holden JE, Proudfit HK. Enkephalin neurons that projectto the A7 catecholamine cell group are located in nucleithat modulate nociception: ventromedial medulla.Neuroscience. 1998;83(3):929–47.

Ikeda M, Tannai T, Matsushita M. Ascending anddescending internuclear connections of the trigeminalsensory nuclei in the cat. A study with the retrogradeand anterograde horseradish peroxidase technique.Neuroscience. 1984;12:1243–60.

Ikeda T, Terayama R, Jue S, Sugiyo S, Dubner R, Ren K.Differential rostral projections of caudal brainstem neu-rons receiving trigeminal input after masseter inflam-mation. J Comp Neurol. 2003;465:220–33.

Ito SI. Possible representation of somatic pain in the ratinsular visceral sensory cortex: a field potential study.Neurosci Lett. 1998;241:171–4.

Iwata K, Kenshalo Jr DR, Dubner R, Nahin RL. Dience-phalic projections from the superficial and deep lami-nae of the medullary dorsal horn in the rat. J CompNeurol. 1992;321:404–20.

Iwata K, Tsuboi Y, Tashiro A, Sakamoto M, Hagiwara S,Kohno M, Sumino R. Mesencephalic projections fromsuperficial and deep laminae of the medullary dorsalhorn. J Oral Sci. 1998;40:159–63.

Iwata K, Tashiro A, Tsuboi Y, Imai T, Sumino R,Morimoto T, Dubner R, Ren K. Medullary dorsalhorn neuronal activity in rats with persistent temporo-mandibular joint and perioral inflammation.J Neurophysiol. 1999;82:1244–53.

Iwata K, Imai T, Tsuboi Y, Tashiro A, Ogawa A,Morimoto T, Masuda Y, Tachibana Y, Hu J. Alterationof medullary dorsal horn neuronal activity followinginferior alveolar nerve transection in rats.J Neurophysiol. 2001;86:2868–77.

Iwata K, Fukuoka T, Kondo E, Tsuboi Y, Tashiro A,Noguchi K, Masuda Y, Morimoto T, Kanda K. Plasticchanges in nociceptive transmission of the rat spinalcord with advancing age. J Neurophysiol.2002;87:1086–93.

Iwata K, Kamo H, Ogawa A, Tsuboi Y, Noma N,Mitsuhashi Y, Taira M, Koshikawa N, Kitagawa J.Anterior cingulate cortical neuronal activity during

20 K. Iwata et al.

Page 21: Neurophysiology of Orofacial Pain - Berandafkg.usu.ac.id/images/Bahan_Kuliah/Buku_McCullough/... · Neurophysiology of Orofacial Pain Koichi Iwata, Mamoru Takeda, Seog Bae Oh, and

perception of noxious thermal stimuli in monkeys.J Neurophysiol. 2005;94:1980–91.

Iwata K, Imamura Y, Honda K, Shinoda M. Physiologicalmechanisms of neuropathic pain: the orofacial region.Int Rev Neurobiol. 2011a;97:227–50.

Iwata K, Miyachi S, Imanishi M, Tsuboi Y, Kitagawa J,Teramoto K, Hitomi S, Shinoda M, Kondo M,Takada M. Ascending multisynaptic pathways fromthe trigeminal ganglion to the anterior cingulate cortex.Exp Neurol. 2011b;227:69–78.

Jacquin M, Chiaia NL, Haring JH, Rhoades RW. Inter sub-nuclear connections within the rat trigeminal brainstemcomplex. Somatosens Mot Res. 1986a; 7:399–420.

Jacquin MF, Renehan WE, Mooney RD, Rhodes RW.Structure-function relationships in rat medullary andcervical dorsal horns. I. Trigeminal primary afferents.J Neurophysiol. 1986b;55:1153–86.

Ji RR, Baba H, Brenner GJ, Woolf CJ. Nociceptive-specific activation of ERK in spinal neurons contributesto pain hypersensitivity. Nat Neurosci. 1999;2:1114–9.

Julius D, Basbaum AI. Molecular mechanisms ofnociception. Nature. 2001;413(6852):203–10.

Kaji K, Shinoda M, Honda K, Unno S, Shimizu N,Iwata K. Connexin 43 contributes to ectopic orofacialpain following inferior alveolar nerve injury. Mol Pain.2016;12.

Katagiri A, Shinoda M, Honda K, Toyofuku A, Sessle BJ,Iwata K. Satellite glial cell P2Y12 receptor in the tri-geminal ganglion is involved in lingual neuropathicpain mechanisms in rats. Mol Pain. 2012;8:23.

Keay KA, Feil K, Gordan BD, Herbaert H, BandlerR. Spinal afferents to functionally distinct peri-aqueductal gray columns in the rat: an anterogradeand retrograde tracing study. J Comp Neuol.1997;385:207–29.

Keller AF, Beggs S, Salter MW, De Koninck Y. Transfor-mation of the output of spinal lamina I neurons afternerve injury and microglia stimulation underlying neu-ropathic pain. Mol Pain. 2007;3:27.

King CD, Wong F, Currie T, Mauderli AP, Fillingim RB,Riley 3rd JL. Deficiency in endogenous modulation ofprolonged heat pain in patients with irritable bowelsyndrome and temporomandibular disorder. Pain.2009;143(3):172–8.

Kiyomoto M, Shinoda M, Okada-Ogawa A, Noma N,Shibuta K, Tsuboi Y, Sessle BJ, Imamura Y, Iwata K.Fractalkine signaling in microglia contributes toectopic orofacial pain following trapezius muscleinflammation. J Neurosci. 2013;33:7667–80.

Koyama T, Tanaka YZ, Mikami A. Nociceptive neurons inthe macaque anterior cingulate activate during antici-pation of pain. Neuroreport. 1998;9:2663–7.

Lau BK, Vaughan CW. Descending modulation of pain:the GABA disinhibition hypothesis of analgesia. CurrOpin Neurobiol. 2014;29:159–64.

Lazarov NE. The neurochemical anatomy of trigeminalprimary afferent neurons. In: Contreras CM, editor.Neuroscience – dealing with frontiers. Rijeka: IntechEurope; 2012.

Malan TP, Mata HP, Porreca F. Spinal GABAA andGABAB receptor pharmacology in a rat model of neu-ropathic pain. Anesthesiology. 2002;96:1161–7.

Mansour A, Fox CA, Akil H, Watson SJ. Opioid-receptormRNA expression in the rat CNS: anatomical andfunctional implications. Trends Neurosci. 1995;18(1):22–9.

Manteniotis S, Lehmann R, Flegel C, Vogel F, Hofreuter A,Schreiner BS, et al. Comprehensive RNA-Seq expres-sion analysis of sensory ganglia with a focus on ionchannels and GPCRs in trigeminal ganglia. PLoS One.2013;8(11):e79523.

Mason P. Medullary circuits for nociceptive modulation.Curr Opin Neurobiol. 2012;22:640–5.

Mickle AD, Shepherd AJ, Mohapatra DP. Sensory TRPchannels: the key transducers of nociception and pain.Prog Mol Biol Transl Sci. 2015;131:73–118.

Milligan ED, Watkins LR. Pathological and protectiverole of glia in chronic pain. Nat Rev Neurosci.2009;10:23–16.

Minami M, Maekawa K, Yabuuchi K, Satoh M. Double insitu hybridization study on coexistence of mu-, delta-and kappa-opioid receptor mRNAs with pre-protachykinin A mRNA in the rat dorsal root ganglia.Brain Res Mol Brain Res. 1995;30(2):203–10.

Mizuno N, Konishi A, Sato M. Localization of masticatorymotoneurons in the cat and rat by means of retrogradeaxonal transport of horseradish peroxidase. J CompNeurol. 1975;164:105–16.

MoayediM,Weissman-Fogel I, CrawleyAP,GoldbergMB,Freeman BV, Tenenbaum HC, et al. Contribution ofchronic pain and neuroticism to abnormal forebrain graymatter in patients with temporomandibular disorder.NeuroImage. 2011;55(1):277–86.

Mulder H, Zhang Y, Danielsen N, Sundler F. Islet amyloidpolypeptide and calcitonin gene-related peptide expres-sion are down-regulated in dorsal root ganglia uponsciatic nerve transection. Brain Res Mol Brain Res.1997;47:322–30.

Nagi K, Pineyro G. Kir3 channel signaling complexes:focus on opioid receptor signaling. Front Cell Neurosci.2014;8:186.

Nakagawa K, Takeda M, Tsuboi Y, Kondo M, Kitagawa J,Matsumoto S, Kobayashi A, Sessle BJ, Shinoda M,Iwata K. Alteration of primary afferent activity follow-ing inferior alveolar nerve transection in rats. Mol Pain.2010;6:9.

Nakata H, Tamura Y, Sakamoto K, Akatsuka K, Hirai M,Inui K, Hoshiyama M, Saitoh Y, Yamamoto T,Katayama Y, Kakigi R. Evoked magnetic fields follow-ing noxious laser stimulation of the thigh in humans.NeuroImage. 2008;42:858–68.

Nash PG, Macefield VG, Klineberg IJ, Murray GM,Henderson LA. Differential activation of the humantrigeminal nuclear complex by noxious andnon-noxious orofacial stimulation. Hum Brain Mapp.2009;30(11): 3772–82.

Noma N, Tsuboi Y, Kondo M, Matsumoto M, Sessle BJ,Kitagawa J, Saito K, Iwata K. Organization of

Neurophysiology of Orofacial Pain 21

Page 22: Neurophysiology of Orofacial Pain - Berandafkg.usu.ac.id/images/Bahan_Kuliah/Buku_McCullough/... · Neurophysiology of Orofacial Pain Koichi Iwata, Mamoru Takeda, Seog Bae Oh, and

pERK-immunoreactive cells in trigeminal spinalnucleus caudalis and upper cervical cord followingcapsaicin injection into oral and craniofacial regionsin rats. J Comp Neurol. 2008;507:1428–40.

Nomura H, Ogawa A, Tashiro A, Morimoto T, Hu JW,Iwata K. Induction of Fos protein-like immunoreactiv-ity in the trigeminal spinal nucleus caudalis and uppercervical cord following noxious and non-noxiousmechanical stimulation of the whisker pad of the ratwith an inferior alveolar nerve transection. Pain.2002;95:225–38.

Okada-Ogawa A, Suzuki I, Sessle BJ, Chiang CY,Salter MW, Dostrovsky JO, Tsuboi Y, Kondo M,Kitagawa J, Kobayashi A, Noma N, Imamura Y,Iwata K. Astroglia in medullary dorsal horn (trigeminalspinal subnucleus caudalis) are involved in trigeminalneuropathic pain mechanisms. J Neurosci.2009;29:11161–71.

Okada-Ogawa A, Nakaya Y, Imamura Y, Kobayashi M,Shinoda M, Kita K, Sessle BJ, Iwata K. Involvement ofmedullary GABAergic system in extraterritorial neuro-pathic pain mechanisms associated with inferior alveo-lar nerve transection. Exp Neurol. 2015;267:42–52.

Okamoto K, Katagiri A, Rahman M, Thompson R,Bereiter DA. Inhibition of temporomandibular jointinput to medullary dorsal horn neurons by 5HT3 recep-tor antagonist in female rats. Neuroscience.2015;299:35–44.

Okubo M, Castro A, Guo W, Zou S, Ren K, Wei F, et al.Transition to persistent orofacial pain after nerveinjury involves supraspinal serotonin mechanisms.J Neurosci. 2013;33(12):5152–61.

Olszewski J. On the anatomical and functional organiza-tion on the trigeminal nucleus. J Comp Neurol.1950;92:401–13.

Ossipov MH, Morimura K, Porreca F. Descending painmodulation and chronification of pain. Curr OpinSupport Palliat Care. 2014;8(2):143–51.

Pertovaara A. Noradrenergic pain modulation. ProgNeurobiol. 2006;80(2):53–83.

Pollema-Mays SL, Centeno MV, Ashford CJ,Apkarian AV, Martina M. Expression of backgroundpotassium channels in rat DRG is cell-specific anddown-regulated in a neuropathic pain model. Mol CellNeurosci. 2013;57:1–9.

Purves D, Augustine G, Fitzpatrick D, Katz L,LaMantia A-S, McNamara JD, Williams SM. Neuro-science. 2nd ed. Sunderland: Sinauer Associates IncPublishers; 2004.

Rahman W, Bauer CS, Bannister K, Vonsy JL,Dolphin AC, Dickenson AH. Descending serotonergicfacilitation and the antinociceptive effects of pregabalinin a rat model of osteoarthritic pain. Mol Pain.2009;5:45.

Rainville P, Carrier B, Hofbauer RK, Bushnell MC,Duncan GH. Dissociation of sensory and affectivedimensions of pain using hypnotic modulation. Pain.1999;82:159–71.

Razook JC, Chandler MJ, Foremann RD. Phrenic afferentinput excites C1-C2 spinal neurons in rats. Pain.1995;63:117–25.

Ren K, Dubner R. The role of trigeminal interpolaris-caudalis transition zone in persistent orofacial pain.Int Rev Neurobiol. 2011;97:207–25.

Schiene K, Tzschentke TM, Schroder W, Christoph T.Mechanical hyperalgesia in rats with diabetic poly-neuropathy is selectively inhibited by local peripheralnociceptin/orphanin FQ receptor and micro-opioidreceptor agonism. Eur J Pharmacol. 2015;754:61–5.

Seidel MF, Muller W. Differential pharmacotherapy forsubgroups of fibromyalgia patients with specific con-sideration of 5-HT3 receptor antagonists. Expert OpinPharmacother. 2011;12(9):1381–91.

Sessle BJ. Neural mechanisms and pathways in craniofa-cial pain. Can J Neurol Sci. 1999;3:S7–11.

Sessle BJ. Acute and chronic craniofacial pain: brainstemmechanisms of nociceptive transmission andneuroplasticity, and their clinical correlates. Crit RevOral Biol Med. 2000;11:57–91.

Sessle BJ. Peripheral and central mechanisms of orofacialinflammatory pain. Int Rev Neurobiol. 2011;97:179–206.

Sessle BJ, Hu JW, Amano N, Zhong G. Convergence ofcutaneous, tooth pulp, visceral, neck and muscle affer-ents onto nociceptive and non-nociceptive neurones intrigeminal subnucleus caudalis (medullary dorsal horn)and its implications for referred pain. Pain. 1986;27(2):219–35.

Shibuta K, Suzuki I, Shinoda M, Tsuboi Y, Honda K,Shimizu N, Sessle BJ, Iwata K. Organization of hyper-active microglial cells in trigeminal spinal subnucleuscaudalis and upper cervical spinal cord associated withorofacial neuropathic pain. Brain Res. 2012;1451:74–86.

Shigenaga Y, Chen IC, Suemune S, Nishimori T,Nasution ID, Yoshida A, Sato H, Okamoto T, Sera M,Hosoi M. Oral and facial representation within themedullary and upper cervical dorsal horns in the cat.J Comp Neurol. 1986;243:388–403.

Shimada SG, LaMotte RH. Behavioral differentiationbetween itch and pain in mouse. Pain. 2008;139(3):681–7.

Sivilotti L, Woolf CJ. The contribution of GABAA andglycine receptors to central sensitization: disinhibitionand touch-evoked allodynia in the spinal cord.J Neurophysiol. 1994;15:333–41.

Snider WD, McMahon SB. Tracking pain at source: newideas about nociceptors. Neuron. 1998;20:629–32.

Stein C, Zollner C. Opioids and sensory nerves. HandbExp Pharmacol. 2009;194:495–518.

Sugimoto T, Takemura M. Tooth-pulp primary neurons:cell size analysis, central connection and carbonicanhydrase activity. Brain Res Bull. 1993;30:221–6.

Sun WH, Chen CC. Roles of proton-sensing receptors inthe transition from acute to chronic pain. J Dent Res.2016;95(2):135–42.

22 K. Iwata et al.

Page 23: Neurophysiology of Orofacial Pain - Berandafkg.usu.ac.id/images/Bahan_Kuliah/Buku_McCullough/... · Neurophysiology of Orofacial Pain Koichi Iwata, Mamoru Takeda, Seog Bae Oh, and

Suzuki R, Rygh LJ, Dickenson AH. Bad news from thebrain: descending 5-HT pathways that control spinalpain processing. Trends Pharmacol Sci. 2004;25(12):613–7.

Suzuki I, Tsuboi Y, Shinoda M, Shibuta K, Honda K,Katagiri A, Kiyomoto M, Sessle BJ, Matsuura S,Ohara K, Urata K, Iwata K. Involvement of ERKphosphorylation of trigeminal spinal subnucleuscaudalis neurons in thermal hypersensitivity in ratswith infraorbital nerve injury. PLoS One. 2013;8:e57278.

TakedaM, Tanimoto T, Matsumoto S. Changes in mechan-ical receptive field properties induced by GABAAreceptor activation in the trigeminal spinal nucleuscaudalis neurons in rats. Exp Brain Res.2000;134:409–16.

TakedaM, Tanimoto T, Ito M, NasuM,Mastumoto S. Roleof capsaicin-sensitive afferent inputs from the massetermuscle in the C1 spinal neurons responding to tooth-pulp stimulation in rats. Exp Brain Res.2005;160:107–17.

Tanimoto T, Takeda M, Matsumoto S. Suppressive effectof vagal afferent on cervical dorsal horn neuronsresponding to tooth-pulp electrical stimulation in therat. Exp Brain Res. 2002;145:468–79.

Tominaga M. The role of TRP channels in thermo-sensation. In: Liedtke WB, Heller S, editors. TRP ionchannel function in sensory transduction and cellularsignaling cascades, Frontiers in neuroscience. BocaRaton: CRC Press; 2007.

Torsney C, MacDermott AB. Disinhibition opens the gateto pathological pain signaling in superficial neurokinin1 receptor-expressing neurons in rat spinal cord.J Neurosci. 2006;26:1833–43.

Treede RD, Kenshalo DR, Gracely RH, Jones AK. Thecortical representation of pain. Pain. 1999;79:105–11.

Tsuboi Y, Takeda M, Tanimoto T, Ikeda M, Matsumoto S,Kitagawa J, Teramoto K, Simizu K, Yamazaki Y,Shima A, Ren K, Iwata K. Alteration of the secondbranch of the trigeminal nerve activity following infe-rior alveolar nerve transection in rats. Pain. 2004;111:323–34.

Vachon-Presseau E, Centeno MV, Ren W, Berger SE,Tetreault P, Ghantous M, Baria A, Farmer M,Baliki MN, Schnitzer TJ, Apkarian AV. The emotionalbrain as a predictor and amplifier of chronic pain.J Dent Res. 2016;95:605–12.

Vogt BA. Pain and emotion interactions in subregions ofthe cingulate gyrus. Nat Rev Neurosci. 2005;6:533–44.

Waite, Tracy. In: Paxinos G, editor. The rat nervous system.2nd ed. Sydney: Academic; 1995. p. 705–24.

Wei F, Dubner R, Zou S, Ren K, Bai G, Wei D, et al.Molecular depletion of descending serotonin unmasksits novel facilitatory role in the development of persis-tent pain. J Neurosci. 2010;30(25):8624–36.

Willis Jr WD. Central nervous system mechanisms forpain modulation. Appl Neurophysiol. 1985;48(1–6):153–65.

Willis WD. Role of neurotransmitters in sensitization ofpain responses. Ann N YAcad Sci. 2001;933:142–56.

Willis Jr WD, Zhang X, Honda CN, Giesler Jr GJ.Projections from the marginal zone and deep dorsalhorn to the ventrobasal nuclei of the primate thalamus.Pain. 2001;92:267–76.

Woo SH, Ranade S, Weyer AD, Dubin AE, Baba Y, Qiu Z,Petrus M, Miyamoto T, Reddy K, Lumpkin EA,Stucky CL, Patapoutian A. Piezo2 is required forMerkel-cell mechanotransduction. Nature. 2014;509:622–6.

Yaksh TL, Rudy TA. Narcotic analgestics: CNS sites andmechanisms of action as revealed by intracerebralinjection techniques. Pain. 1978;4(4):299–359.

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